Responsive polymeric receptors with applications in diagnostics and therapeutic development

Lead Research Organisation: Durham University
Department Name: Chemistry

Abstract

Many pathogens cause disease through the production of carbohydrate-binding proteins (lectins) which interact with mammalian cell surface glycans. This recognition is often key to processes of colonisation or toxicity, and could be exploited to provide crucial diagnostic information to identify or monitor the progression of disease, in addition to offering new scope for the development of therapeutics. Interactions between lectins and carbohydrates are typically weak (mM - muM Kd), but their effects can be enhanced significantly through multivalent effects. The use of synthetic polymer scaffolds in the construction of receptors provides convenient access to the large interface areas required to interact at multiple binding sites, and can allow for the incorporation of additional functionality, including the attachment of fluorescent reporting groups, or incorporating the ability to respond to external stimuli.

We have recently demonstrated that multivalent glycopolymers constructed on a thermoresponsive polymer scaffold can be used to 'catch-and- release' the carbohydrate recognition domain of the cholera toxin, facilitating its selective capture in complex media (C. S. Mahon, G. C. Wildsmith, D. Haksar, E. de Poel, J. M. Beekman, R. J. Pieters, M. E. Webb and W. B. Turnbull, Faraday Discuss., 2019, 219, 112-117). Here, we will develop similar polymeric receptors to allow for the production of sensors which can respond to the presence of other target lectins by changing their optical or fluorescence properties. The glycan recognition preferences of many disease-associated lectins are known, and it is proposed that by incorporating multiple recognition units on polymeric scaffolds, sensors of high sensitivity may be prepared. Polymer scaffolds will be synthesised using controlled radical polymerisation techniques with monomer units selected to provide points of attachment for carbohydrate recognition units, allowing functionalisation of receptors directly from the reducing sugars. The incorporation of stimuli-responsive units into the polymer backbone can enable release of the analyte on demand after detection, facilitating further detailed characterisation, and simultaneously regenerating the sensing platform for further use (E. E. Antunez, C. S. Mahon, Z. Tong, N. H. Voelcker and M. Mullner, Biomacromolecules, 2020, DOI: 10.1021/acs.biomac.0c01318).

The development of high-affinity receptors for these proteins implicated in disease progression could also be exploited in the development of new therapeutics. Given the acceleration of antibiotic resistance, there is an increasing drive towards the generation of new therapeutics that act on bacterial virulence, rather than exert a bactericidal effect. Compounds which inhibit these key recognition processes which enable colonisation or toxicity by offering an alternative surface for high-affinity binding offer an attractive antibiotic-free route to combatting bacterial disease.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/T518001/1 01/10/2020 30/09/2025
2457282 Studentship EP/T518001/1 01/10/2020 31/12/2023 Helen Patricia Sims